RESUMEN
The composition of skeletal muscle fiber types affects the quality of livestock meat and human athletic performance and health. L-arginine (Arg), a semi-essential amino acid, has been observed to promote the formation of slow-twitch muscle fibers in animal models. However, the precise molecular mechanisms are still unclear. This study investigates the role of Arg in skeletal muscle fiber composition and mitochondrial function through the mTOR signaling pathway. In vivo, 4-week C56BL/6J male mice were divided into three treatment groups and fed a basal diet supplemented with different concentrations of Arg in their drinking water. The trial lasted 7 weeks. The results show that Arg supplementation significantly improved endurance exercise performance, along with increased SDH enzyme activity and upregulated expression of the MyHC I, MyHC IIA, PGC-1α, and NRF1 genes in the gastrocnemius (GAS) and quadriceps (QUA) muscles compared to the control group. In addition, Arg activated the mTOR signaling pathway in the skeletal muscle of mice. In vitro experiments using cultured C2C12 myotubes demonstrated that Arg elevated the expression of slow-fiber genes (MyHC I and Tnnt1) as well as mitochondrial genes (PGC-1α, TFAM, MEF2C, and NRF1), whereas the effects of Arg were inhibited by the mTOR inhibitor rapamycin. In conclusion, these findings suggest that Arg modulates skeletal muscle fiber type towards slow-twitch fibers and enhances mitochondrial functions by upregulating gene expression through the mTOR signaling pathway.
Asunto(s)
Arginina , Fibras Musculares Esqueléticas , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal/efectos de los fármacos , Ratones , Arginina/metabolismo , Arginina/farmacología , Masculino , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/efectos de los fármacos , Ratones Endogámicos C57BL , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/efectos de los fármacos , Línea CelularRESUMEN
Piperine has been shown to bind to myosin and shift the distribution of conformational states of myosin molecules from the super-relaxed state to the disordered relaxed state. However, little is known about the implications for muscle force production and potential underlying mechanisms. Muscle contractility experiments were performed using isolated muscles and single fibres from rats and mice. The dose-response effect of piperine on muscle force was assessed at several stimulation frequencies. The potentiation of muscle force was also tested in muscles fatigued by eccentric contractions. Potential mechanisms of force potentiation were assessed by measuring Ca2+ levels during stimulation in enzymatically dissociated muscle fibres, while myofibrillar Ca2+ sensitivity was assessed in chemically skinned muscle fibres. Piperine caused a dose-dependent increase in low-frequency force with no effect on high-frequency force in both slow- and fast-twitch muscle, with similar relative increases in twitch force, rate of force development and relaxation rate. The potentiating effect of piperine on low-frequency force was reversible, and piperine partially recovered low-frequency force in fatigued muscle. Piperine had no effect on myoplasmic free [Ca2+] levels in mouse muscle fibres, whereas piperine substantially augmented the force response to submaximal levels of [Ca2+] in rat MyHCII fibres and MyHCI fibres along with a minor increase in maximum Ca2+-activated force. Piperine enhances low-frequency force production in both fast- and slow-twitch muscle. The effects are reversible and can counteract muscle fatigue. The primary underlying mechanism appears to be an increase in Ca2+ sensitivity. KEY POINTS: Piperine is a plant alkaloid derived from black pepper. It is known to bind to skeletal muscle myosin and enhance resting ATP turnover but its effects on contractility are not well known. We showed for the first time a piperine-induced force potentiation that was pronounced during low-frequency electrical stimulation of isolated muscles. The effect of piperine was observed in both slow and fast muscle types, was reversible, and could counteract the force decrements observed after fatiguing muscle contractions. Piperine treatment caused an increase in myofibrillar Ca2+ sensitivity in chemically skinned muscle fibres, while we observed no effect on intracellular Ca2+ concentrations during electrical stimulation in enzymatically dissociated muscle fibres.
Asunto(s)
Alcaloides , Benzodioxoles , Calcio , Contracción Muscular , Fibras Musculares de Contracción Rápida , Fibras Musculares de Contracción Lenta , Piperidinas , Alcamidas Poliinsaturadas , Animales , Alcamidas Poliinsaturadas/farmacología , Benzodioxoles/farmacología , Piperidinas/farmacología , Alcaloides/farmacología , Ratones , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Rápida/fisiología , Ratas , Contracción Muscular/efectos de los fármacos , Masculino , Calcio/metabolismo , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Fibras Musculares de Contracción Lenta/fisiología , Fatiga Muscular/efectos de los fármacos , Fatiga Muscular/fisiología , Ratones Endogámicos C57BL , Ratas Sprague-Dawley , Relación Dosis-Respuesta a DrogaRESUMEN
Previous research has shown that leucine (Leu) can stimulate and enhance the proliferation of equine skeletal muscle satellite cells (SCs). The gene expression profile associated with Leu-induced proliferation of equine SCs has also been documented. However, the specific role of Leu in regulating the expression of slow-twitch muscle fibers (slow-MyHC) and mitochondrial function in equine SCs, as well as the underlying mechanism, remains unclear. During this investigation, equine SCs underwent culturing in differentiation medium and were subjected to varying concentrations of Leu (0 mM, 0.5 mM, 1 mM, 2 mM, 5 mM, and 10 mM) over a span of 3 days. AMP-activated protein kinase (AMPK) inhibitor Compound C and mammalian target of rapamycin complex (mTOR) inhibitor Rapamycin were utilized to explore its underlying mechanism. Here we showed that the expression of slow-MyHC at 2 mM Leu level was significantly higher than the concentration levels of 0 mM,0.5 mM and 10 mM (P <0.01), and there was no significant difference compared to other groups (P > 0.05); the basal respiration, maximum respiration, standby respiration and the expression of slow-MyHC, PGC-1α, Cytc, ND1, TFAM, and COX1 were significantly increased with Leu supplementation (P < 0.01). We also found that Leu up-regulated the expression of key proteins on AMPK and mTOR signaling pathways, including LKB1, p-LKB1, AMPK, p-AMPK, S6, p-S6, 4EBP1, p-4EBP1, mTOR and p-mTOR (P < 0.05 or P < 0.01). Notably, when we treated the equine SCs with the AMPK inhibitor Compound C and the mTOR inhibitor Rapamycin, we observed a reduction in the beneficial effects of Leu on the expression of genes related to slow-MyHC and signaling pathway-related gene expressions. This study provides novel evidence that Leu promotes slow-MyHC expression and enhances mitochondrial function in equine SCs through the AMPK/mTOR signaling pathways, shedding light on the underlying mechanisms involved in these processes for the first time.
Asunto(s)
Proteínas Quinasas Activadas por AMP , Metabolismo Energético , Leucina , Fibras Musculares de Contracción Lenta , Células Satélite del Músculo Esquelético , Transducción de Señal , Serina-Treonina Quinasas TOR , Animales , Leucina/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Células Satélite del Músculo Esquelético/metabolismo , Células Satélite del Músculo Esquelético/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Caballos , Proteínas Quinasas Activadas por AMP/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Metabolismo Energético/efectos de los fármacos , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Células CultivadasRESUMEN
The conversion of fast-twitch fibers into slow-twitch fibers within skeletal muscle plays a crucial role in improving physical stamina and safeguarding against metabolic disorders in individuals. Grape seed proanthocyanidin extract (GSPE) possesses numerous pharmacological and health advantages, effectively inhibiting the onset of chronic illnesses. However, there is a lack of research on the specific mechanisms by which GSPE influences muscle physiology and gut microbiota. This study aims to investigate the role of gut microbiota and their metabolites in GSPE regulation of skeletal muscle fiber type conversion. In this experiment, 54 male BALB/c mice were randomly divided into three groups: basal diet, basal diet supplemented with GSPE, and basal diet supplemented with GSPE and antibiotics. During the feeding period, glucose tolerance and forced swimming tests were performed. After euthanasia, samples of muscle and feces were collected for analysis. The results showed that GSPE increased the muscle mass and anti-fatigue capacity of the mice, as well as the expression of slow-twitch fibers. However, the beneficial effects of GSPE on skeletal muscle fibers disappeared after adding antibiotics to eliminate intestinal microorganisms, suggesting that GSPE may play a role by regulating intestinal microbial structure. In addition, GSPE increased the relative abundance of Blautia, Muribaculaceae, and Enterorhabdus, as well as butyrate production. Importantly, these gut microbes exhibited a significant positive correlation with the expression of slow-twitch muscle fibers. In conclusion, supplementation with GSPE can increase the levels of slow-twitch fibers by modulating the gut microbiota, consequently prolonging the duration of exercise before exhaustion. PRACTICAL APPLICATION: This research suggests that grape seed proanthocyanidin extract (GSPE) has potential applications in improving physical stamina and preventing metabolic disorders. By influencing the gut microbiota and increasing butyric acid production, GSPE contributes to the conversion of fast-twitch muscle fibers into slow-twitch fibers, thereby enhancing anti-fatigue capacity and exercise endurance. While further studies are needed, incorporating GSPE into dietary supplements or functional foods could support individuals seeking to optimize their exercise performance and overall metabolic health.
Asunto(s)
Ácido Butírico , Microbioma Gastrointestinal , Extracto de Semillas de Uva , Ratones Endogámicos BALB C , Proantocianidinas , Animales , Proantocianidinas/farmacología , Masculino , Microbioma Gastrointestinal/efectos de los fármacos , Extracto de Semillas de Uva/farmacología , Ratones , Ácido Butírico/metabolismo , Ácido Butírico/farmacología , Ciego/microbiología , Ciego/metabolismo , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Rápida/metabolismo , Músculo Esquelético/efectos de los fármacos , Bacterias/efectos de los fármacos , Bacterias/clasificaciónRESUMEN
Sarcopenia is a musculoskeletal disease that reduces muscle mass and strength in older individuals. The study investigates the effects of azilsartan (AZL) on skeletal muscle loss in natural sarcopenic rats. Male Sprague-Dawley rats aged 4-6 months and 18-21 months were selected as young-matched control and natural-aged (sarcopenic) rats, respectively. Rats were allocated into young and old control (YC and OC) and young and old AZL treatment (YT and OT) groups, which received vehicles and AZL (8 mg/kg, orally) for 6 weeks. Rats were then sacrificed after muscle function analysis. Serum and gastrocnemius (GN) muscles were isolated for further endpoints. AZL significantly improved muscle grip strength and antioxidant levels in sarcopenic rats. AZL also restored the levels of insulin, testosterone, and muscle biomarkers such as myostatin and creatinine kinase in sarcopenic rats. Furthermore, AZL treatment improved the cellular and ultrastructure of GN muscle and prevented the shift of type II (glycolytic) myofibers to type I (oxidative) myofibers. The results showed that AZL intervention restored protein synthesis in natural sarcopenic rats by increasing p-Akt-1 and decreasing muscle RING-finger protein-1 and tumor necrosis factor alpha immunoexpressions. In conclusion, the present findings showed that AZL could be an effective intervention in treating age-related muscle impairments.
Asunto(s)
Envejecimiento , Bencimidazoles , Fibras Musculares de Contracción Rápida , Fibras Musculares de Contracción Lenta , Oxadiazoles , Ratas Sprague-Dawley , Sarcopenia , Animales , Sarcopenia/prevención & control , Sarcopenia/metabolismo , Sarcopenia/tratamiento farmacológico , Sarcopenia/patología , Masculino , Oxadiazoles/farmacología , Oxadiazoles/uso terapéutico , Envejecimiento/efectos de los fármacos , Ratas , Bencimidazoles/farmacología , Bencimidazoles/uso terapéutico , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/patología , Fuerza Muscular/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Miostatina/metabolismo , Antioxidantes/farmacologíaRESUMEN
Skeletal muscle is a heterogeneous tissue composed of a variety of functionally different fiber types. Slow-twitch type I muscle fibers are rich with mitochondria, and mitochondrial biogenesis promotes a shift towards more slow fibers. Leucine, a branched-chain amino acid (BCAA), regulates slow-twitch muscle fiber expression and mitochondrial function. The BCAA content is increased in porcine whole-blood protein hydrolysates (PWBPH) but the effect of PWBPH on muscle fiber type conversion is unknown. Supplementation with PWBPH (250 and 500 mg/kg for 5 weeks) increased time to exhaustion in the forced swimming test and the mass of the quadriceps femoris muscle but decreased the levels of blood markers of exercise-induced fatigue. PWBPH also promoted fast-twitch to slow-twitch muscle fiber conversion, elevated the levels of mitochondrial biogenesis markers (SIRT1, p-AMPK, PGC-1α, NRF1 and TFAM) and increased succinate dehydrogenase and malate dehydrogenase activities in ICR mice. Similarly, PWBPH induced markers of slow-twitch muscle fibers and mitochondrial biogenesis in C2C12 myotubes. Moreover, AMPK and SIRT1 inhibition blocked the PWBPH-induced muscle fiber type conversion in C2C12 myotubes. These results indicate that PWBPH enhances exercise performance by promoting slow-twitch muscle fiber expression and mitochondrial function via the AMPK/SIRT1 signaling pathway.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Fibras Musculares de Contracción Lenta/metabolismo , Biogénesis de Organelos , Condicionamiento Físico Animal , Hidrolisados de Proteína/farmacología , Sirtuina 1/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Animales , Masculino , Ratones , Ratones Endogámicos ICR , Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Transducción de Señal , Sirtuina 1/genética , PorcinosRESUMEN
There has been a concern that sodium-glucose cotransporter 2 (SGLT2) inhibitors could reduce skeletal muscle mass and function. Here, we examine the effect of canagliflozin (CANA), an SGLT2 inhibitor, on slow and fast muscles from nondiabetic C57BL/6J mice. In this study, mice were fed with or without CANA under ad libitum feeding, and then evaluated for metabolic valuables as well as slow and fast muscle mass and function. We also examined the effect of CANA on gene expressions and metabolites in slow and fast muscles. During SGLT2 inhibition, fast muscle function is increased, as accompanied by increased food intake, whereas slow muscle function is unaffected, although slow and fast muscle mass is maintained. When the amount of food in CANA-treated mice is adjusted to that in vehicle-treated mice, fast muscle mass and function are reduced, but slow muscle was unaffected during SGLT2 inhibition. In metabolome analysis, glycolytic metabolites and ATP are increased in fast muscle, whereas glycolytic metabolites are reduced but ATP is maintained in slow muscle during SGLT2 inhibition. Amino acids and free fatty acids are increased in slow muscle, but unchanged in fast muscle during SGLT2 inhibition. The metabolic effects on slow and fast muscles are exaggerated when food intake is restricted. This study demonstrates the differential effects of an SGLT2 inhibitor on slow and fast muscles independent of impaired glucose metabolism, thereby providing new insights into how they should be used in patients with diabetes, who are at a high risk of sarcopenia.
Asunto(s)
Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Adenilato Quinasa/biosíntesis , Adenilato Quinasa/genética , Tejido Adiposo Blanco/efectos de los fármacos , Aminoácidos/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Canagliflozina/farmacología , Ingestión de Alimentos/efectos de los fármacos , Ácidos Grasos no Esterificados/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Ontología de Genes , Glucólisis , Fuerza de la Mano , Hígado/efectos de los fármacos , Masculino , Metaboloma/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Fibras Musculares de Contracción Rápida/metabolismo , Músculo Esquelético/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transportador 2 de Sodio-Glucosa/fisiología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Serina-Treonina Quinasas TOR/biosíntesis , Serina-Treonina Quinasas TOR/genéticaRESUMEN
Ellagic acid (EA) is a natural polyphenolic compound, which shows various effects, such as anti-inflammatory and antioxidant effects and inhibition of platelet aggregation. In this study, we investigated the effect of EA on muscle endurance and explored its possible underlying mechanism. Our data showed that EA significantly improved muscle endurance in mice. EA increased the protein level of slow myosin heavy chain (MyHC) I and decreased the protein level of fast MyHC. We also found that the AMP-activated protein kinase (AMPK) signaling pathway was activated by EA. Finally, our data indicated that EA could increase mitochondrial biogenesis and function by increasing the content of mitochondrial DNA (mtDNA), the concentration of ATP, the activities of succinodehydrogenase (SDH) and malate dehydrogenase (MDH), and the mRNA levels of ATP synthase (ATP5G), mtDNA transcription factor A (TFAM), mitochondrial transcription factor b1 (Tfb1m) and citrate synthase (Cs) in mice and C2C12 myotubes. These results proved that EA could enhance muscle endurance via transforming the muscle fiber type and improving mitochondrial biogenesis and function.
Asunto(s)
Ácido Elágico/farmacología , Músculo Esquelético/efectos de los fármacos , Animales , Animales no Consanguíneos , Masculino , Ratones , Modelos Animales , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Cadenas Pesadas de Miosina/metabolismoRESUMEN
Lycopene has a wide range of biological functions, especially its antioxidant capacity. However, effects of lycopene on muscle fatigue resistant and muscle fiber type conversion are unknown. In this study, we found that lycopene significantly prolonged the swimming time to exhaustion in mice. We also showed that lycopene increased the proportion of slow-twitch muscle fiber by promoting muscle fiber type conversion from fast-twitch to slow-twitch in mice and in C2C12 myotubes. The AMP-activated protein kinase (AMPK) signaling was activated by lycopene. AMPK upstream and downstream regulators including nuclear respiratory factor 1, calcium calmodulin-dependent protein kinase kinase-ß, sirtuin 1 and peroxisome proliferator activated receptor-γ coactivator-1É were also increased by lycopene. AMPK inhibitor compound C markedly attenuated the lycopene-induced skeletal muscle fiber type conversion in C2C12 myotubes. Taken together, we provided the first evidence that lycopene increases the proportion of slow-twitch muscle fiber through AMPK signaling pathway to improve fatigue resistant of skeletal muscle.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Licopeno/farmacología , Fatiga Muscular/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/genética , Animales , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/genética , Quinasa de la Proteína Quinasa Dependiente de Calcio-Calmodulina/metabolismo , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Ratones , Factor Nuclear 1 de Respiración/genética , Factor Nuclear 1 de Respiración/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismoRESUMEN
This study aimed to investigate the role and underlying molecular mechanism of quercetin in regulating skeletal muscle fiber type transition. We found that dietary quercetin supplementation in mice significantly increased oxidative fiber-related gene expression, slow-twitch fiber percentage and succinic dehydrogenase (SDH) activity. By contrast, quercetin decreased lactate dehydrogenase (LDH) activity, fast MyHC protein expression, fast-twitch fiber percentage, and MyHC IIb mRNA expression. Furthermore, quercetin significantly increased serum adiponectin (AdipoQ) concentration, and the expression levels of AdipoQ and AdipoR1. However, inhibition of adiponectin signaling by AdipoR1 siRNA significantly attenuated the effects of quercetin on muscle fiber type-related gene expression, the percentages of slow MyHC-positive and fast MyHC-positive fibers, and metabolic enzyme activity in C2C12 myotubes. Together, our data indicated that quercetin could promote skeletal fiber switching from glycolytic type II to oxidative type I through AdipoQ signaling.
Asunto(s)
Adiponectina/metabolismo , Fibras Musculares de Contracción Rápida , Fibras Musculares de Contracción Lenta , Quercetina/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Línea Celular , Suplementos Dietéticos , Expresión Génica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos BALB C , Fibras Musculares de Contracción Rápida/química , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Lenta/química , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Fibras Musculares de Contracción Lenta/metabolismo , Quercetina/administración & dosificaciónRESUMEN
AIMS/INTRODUCTION: Myopathy is a common complication of any diabetes type, consisting in failure to preserve mass and muscular function. Oxidative stress has been considered one of the main causes for this condition. This study aimed to search if Nicorandil, a KATP channel opener, could protect slow- and fast-twitch diabetic rat muscles from oxidative stress, and to unveil its possible mechanisms. MATERIALS AND METHODS: Diabetes was induced in male Wistar rats by applying intraperitoneally streptozotocin (STZ) at 100 mg/kg doses. Nicorandil (3 mg/kg/day) was administered along 4 weeks. An insulin tolerance test and assessment of fasting blood glucose (FBG), TBARS, reduced (GSH), and disulfide (GSSG) glutathione levels, GSH/GSSG ratio, and mRNA expression of glutathione metabolism-related genes were performed at end of treatment in soleus and gastrocnemius muscles. RESULTS: Nicorandil significantly reduced FBG levels and enhanced insulin tolerance in diabetic rats. In gastrocnemius and soleus muscles, Nicorandil attenuated the oxidative stress by decreasing lipid peroxidation (TBARS), increasing total glutathione and modulating GPX1-mRNA expression in both muscle's types. Nicorandil also increased GSH and GSH/GSSG ratio and downregulated the GCLC- and GSR-mRNA in gastrocnemius, without significative effect on those enzymes' mRNA expression in diabetic soleus muscle. CONCLUSIONS: In diabetic rats, Nicorandil attenuates oxidative stress in slow- and fast-twitch skeletal muscles by improving the glutathione system functioning. The underlying mechanisms for the modulation of glutathione redox state and the transcriptional expression of glutathione metabolism-related genes seem to be fiber type-dependent.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Nicorandil/farmacología , Estrés Oxidativo/efectos de los fármacos , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Glutatión/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Músculo Esquelético/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Ratas , Ratas Wistar , Estreptozocina , Transcripción Genética/efectos de los fármacosRESUMEN
Puerarin is an isoflavonoid extracted from Pueraria lobate with extensive pharmacological effects in traditional Chinese medicine. The evidence implicates that puerarin mitigates hyperglycemia and various relevant complications. Here, the effect of puerarin on skeletal muscle wasting induced by type 1 diabetes (T1D) was explored. Streptozotocin (STZ)-induced T1D male Sprague Dawley (SD) rats were used in this study. Muscle strength, weight and size were measured. L6 rat skeletal muscle cells were applied for in vitro study. Our results showed that eight-week oral puerarin administration (100â¯mg/kg) increased muscle strengths and weights accompanied by enhanced skeletal muscle cross-sectional areas in diabetic rats. Simultaneously, puerarin also reduced expressions of several muscle wasting marker genes including F-box only protein 32 (Atrogin-1) and muscle-specific RING-finger 1 (Murf-1) in diabetic group both in vitro and in vivo. Transformation from type I fibers (slow muscle) to type II fibers (fast muscle) were also observed under puerarin administration in diabetic rats. Puerarin promoted Akt/mTOR while inhibited LC3/p62 signaling pathway in skeletal muscle cells. In conclusion, our study showed that puerarin mitigated skeletal muscle wasting in T1D rats and closely related with Akt/mTOR activation and autophagy inhibition. Whether this effect in murine applies to humans remains to be determined.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Isoflavonas/farmacología , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Atrofia Muscular/prevención & control , Animales , Glucemia/metabolismo , Línea Celular , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/inducido químicamente , Masculino , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/patología , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fuerza Muscular/efectos de los fármacos , Atrofia Muscular/etiología , Atrofia Muscular/metabolismo , Atrofia Muscular/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Proteínas Ligasas SKP Cullina F-box/genética , Proteínas Ligasas SKP Cullina F-box/metabolismo , Estreptozocina , Serina-Treonina Quinasas TOR/metabolismo , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Age-related sarcopenia is associated with a variety of changes in skeletal muscle. These changes are interrelated with each other and associated with systemic metabolism, the details of which, however, are largely unknown. Eicosapentaenoic acid (EPA) is a promising nutrient against sarcopenia and has multifaceted effects on systemic metabolism. In this study, we hypothesized that the aging process in skeletal muscle can be intervened by the administration of EPA. Seventy-five-week-old male mice were assigned to groups fed an EPA-deprived diet (EPA-) or an EPA-enriched diet with 1 wt% EPA (EPA+) for 12 wk. Twenty-four-week-old male mice fed with normal chow were also analyzed. At baseline, the grip strength of the aging mice was lower than that of the young mice. After 12 wk, EPA+ showed similar muscle mass but increased grip strength compared with EPA-. EPA+ displayed higher insulin sensitivity than EPA-. Immunohistochemistry and gene expression analysis of myosin heavy chains (MyHCs) revealed fast-to-slow fiber type transition in aging muscle, which was partially inhibited by EPA. RNA sequencing (RNA-Seq) analysis suggested that EPA supplementation exerts pathway-specific effects in skeletal muscle including the signatures of slow-to-fast fiber type transition. In conclusion, we revealed that aging skeletal muscle in male mice shows lower grip strength and fiber type changes, both of which can be inhibited by EPA supplementation irrespective of muscle mass alteration.NEW & NOTEWORTHY This study demonstrated that the early phenotype of skeletal muscle in aging male mice is characterized by muscle weakness with fast-to-slow fiber type transition, which could be ameliorated by feeding with EPA-enriched diet. EPA induced metabolic changes such as an increase in systemic insulin sensitivity and altered muscle transcriptome in the aging mice. These changes may be related to the fiber type transition and influence muscle quality.
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Envejecimiento , Ácido Eicosapentaenoico/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Lenta/metabolismo , Proteínas Musculares/metabolismo , Transcriptoma/efectos de los fármacos , Animales , Resistencia a la Insulina , Masculino , Ratones , Ratones Endogámicos C57BL , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Proteínas Musculares/genéticaRESUMEN
Thyroid hormones are important for homeostatic control of energy metabolism and body temperature. Although skeletal muscle is considered a key site for thyroid action, the contribution of thyroid hormone receptor signaling in muscle to whole-body energy metabolism and body temperature has not been resolved. Here, we show that T3-induced increase in energy expenditure requires thyroid hormone receptor alpha 1 (TRα1 ) in skeletal muscle, but that T3-mediated elevation in body temperature is achieved in the absence of muscle-TRα1 . In slow-twitch soleus muscle, loss-of-function of TRα1 (TRαHSACre ) alters the fiber-type composition toward a more oxidative phenotype. The change in fiber-type composition, however, does not influence the running capacity or motivation to run. RNA-sequencing of soleus muscle from WT mice and TRαHSACre mice revealed differentiated transcriptional regulation of genes associated with muscle thermogenesis, such as sarcolipin and UCP3, providing molecular clues pertaining to the mechanistic underpinnings of TRα1 -linked control of whole-body metabolic rate. Together, this work establishes a fundamental role for skeletal muscle in T3-stimulated increase in whole-body energy expenditure.
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Metabolismo Energético/efectos de los fármacos , Fibras Musculares de Contracción Rápida/fisiología , Fibras Musculares de Contracción Lenta/fisiología , Músculo Esquelético/fisiología , Receptores alfa de Hormona Tiroidea/fisiología , Hormonas Tiroideas/farmacología , Animales , Masculino , Ratones , Ratones Noqueados , Fibras Musculares de Contracción Rápida/citología , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Lenta/citología , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Músculo Esquelético/citología , Músculo Esquelético/efectos de los fármacos , Condicionamiento Físico Animal , TranscriptomaRESUMEN
Radix astragali is a popular traditional herbal medicine that provides significant protection against tissue injury in various models of oxidative stress-related diseases. In this study, we aimed to investigate whether administration of Radix astragali prevented atrophy in both slow- and fast-twitch muscles following cast immobilization. Twenty-seven 12-week-old male F344 rats were divided into three experimental groups: control (CON), immobilized (IM), and immobilized with Radix astragali administration (IM+AR). Rats in the IM and IM+AR groups were subjected to immobilization of both lower extremities using casting-tape for 14 days. Rats in the IM+AR group were orally administered a decoction of Radix astragali daily for 21 days beginning 7 days before cast immobilization. As expected, rats in the IM group showed significant decreases (P < 0.05) in soleus and plantaris muscle-to-body weight ratios by 74.3% and 70.5%, respectively, compared with those in the CON group. Administration of Radix astragali significantly reversed (+35.5%) the weight reduction observed in soleus muscle, but not in the plantaris muscle, compared with that in the IM group. Furthermore, administration of Radix astragali inhibited MuRF1 mRNA expression only in the soleus muscle during cast immobilization. Our results demonstrated that administration of Radix astragali suppressed the immobilization-induced reductions in skeletal muscle mass and expression of MuRF1 mRNA in slow-twitch soleus muscles, but not in fast-twitch plantaris muscles.
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Medicamentos Herbarios Chinos/farmacología , Fibras Musculares de Contracción Rápida/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Atrofia Muscular/tratamiento farmacológico , Animales , Astragalus propinquus , Expresión Génica , Miembro Posterior , Inmovilización/efectos adversos , Inmovilización/métodos , Masculino , Fibras Musculares de Contracción Rápida/metabolismo , Fibras Musculares de Contracción Rápida/patología , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/patología , Proteínas Musculares/antagonistas & inhibidores , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Atrofia Muscular/etiología , Atrofia Muscular/genética , Atrofia Muscular/patología , Tamaño de los Órganos/efectos de los fármacos , Fitoterapia/métodos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Endogámicas F344 , Proteínas de Motivos Tripartitos/antagonistas & inhibidores , Proteínas de Motivos Tripartitos/genética , Proteínas de Motivos Tripartitos/metabolismo , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
It has been demonstrated that skeletal muscle adaptions, including muscle fibers transition, angiogenesis, and mitochondrial biogenesis are involved in the regular exercise-induced improvement of endurance capacity and metabolic status. Herein, we investigated the effects of pterostilbene (PST) supplementation on skeletal muscle adaptations to exercise training in rats. Six-week-old male Sprague Dawley rats were randomly divided into a sedentary control group (Sed), an exercise training group (Ex), and exercise training combined with 50 mg/kg PST (Ex + PST) treatment group. After 4 weeks of intervention, an exhaustive running test was performed, and muscle fiber type transformation, angiogenesis, and mitochondrial content in the soleus muscle were measured. Additionally, the effects of PST on muscle fiber transformation, paracrine regulation of angiogenesis, and mitochondrial function were tested in vitro using C2C12 myotubes. In vivo study showed that exercise training resulted in significant increases in time-to-exhaustion, the proportion of slow-twitch fibers, muscular angiogenesis, and mitochondrial biogenesis in rats, and these effects induced by exercise training could be augmented by PST supplementation. Moreover, the in vitro study showed that PST treatment remarkably promoted slow-twitch fibers formation, angiogenic factor expression, and mitochondrial function in C2C12 myotubes. Collectively, our results suggest that PST promotes skeletal muscle adaptations to exercise training thereby enhancing the endurance capacity.
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Fibras Musculares Esqueléticas/efectos de los fármacos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Condicionamiento Físico Animal/fisiología , Estilbenos/uso terapéutico , Animales , Masculino , Fibras Musculares de Contracción Lenta/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Dimer procyanidin B2 [epicatechin-(4ß-8)-epicatechin] (PB2) has attracted a lot of interest in nutrition and medicine because of its significant health-promoting abilities. However, the function of PB2 on different types of skeletal myofiber is still unclear. Here, we have found that PB2 significantly increased protein expression of the slow myosin heavy chain (MyHC) and decreased fast MyHC protein in C2C12 myotubes, accompanied by upregulation of mRNA expression of MyHC I, MyHC IIa, and Tnni1 and downregulation of MyHC IIx and MyHC IIb. We have also found that PB2 enhanced the activities of malate dehydrogenase and succinic dehydrogenase and reduced lactate dehydrogenase activity. PB2 promoted phosphorylation of AMPK and significantly increased mRNA expression of AMPKα1. The upstream factors of AMPK, such as phospho-LKB1, NRF1, and CaMKKß, and the downstream factors of AMPK, including Sirt1 and PGC-1α, were also increased by PB2. Specific suppression of AMPK signaling by AMPKα1 siRNA or by AMPK inhibitor compound C significantly attenuated the PB2-induced upregulation of phospho-AMPK, PGC-1α, and slow MyHC and downregulation of fast MyHC. Our findings suggested that PB2 promotes skeletal slow-twitch myofiber gene expression through the AMPK signaling pathway in C2C12 myotubes.
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Proteínas Quinasas Activadas por AMP/metabolismo , Biflavonoides/farmacología , Catequina/farmacología , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efectos de los fármacos , Proantocianidinas/farmacología , Proteínas Quinasas Activadas por AMP/genética , Animales , Línea Celular , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Fibras Musculares de Contracción Lenta/metabolismo , Músculo Esquelético/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Lycium barbarum berry (gouqi, Goji, goji berry, or wolfberry), a traditional medicine and functional food, has a wide range of biological effects, including immuno-modulation, anti-aging, antitumor, neuro-protection, and hepato-protection. However, thus far, little is known about the traditional effects of L. barbarum on strengthening muscles. Therefore, this study focused on the effects of an extract of L. barbarum on skeletal muscles. First, the extract of L. barbarum significantly increased the mass of the tibial anterior muscle and gastrocnemius muscle and improved the average running distance of mice. Then, in vivo and in vitro experiments showed that the extract enhanced muscle endurance by increasing the proportion of type IIa oxidative muscle fibers and aerobic respiration. In an in-depth study of the molecular mechanism of these effects, we found that the extract upregulated the proportion of type IIa oxidative muscle fibers by activating ERRγ and that the PKA-CREB signaling pathway was involved in its activation. This study is the first to show that L. barbarum extract modulates skeletal muscle remodeling and has mimetic effects on skeletal muscles in a manner similar to exercise. It provides a scientific explanation based on modern biological technologies and concepts for the traditional function of L. barbarum in improving muscle fitness. This study lays a theoretical foundation for the application of L. barbarum in skeletal muscles as an exercise mimetic.
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Frutas/química , Lycium/química , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Músculo Esquelético/efectos de los fármacos , Extractos Vegetales/farmacología , Receptores de Estrógenos/metabolismo , Animales , Masculino , Ratones Endogámicos C57BL , Fibras Musculares de Contracción Lenta/metabolismo , Fibras Musculares de Contracción Lenta/fisiología , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Condicionamiento Físico Animal/fisiología , Transducción de Señal/efectos de los fármacosRESUMEN
The present study aimed to investigate whether arginine (Arg) promotes porcine type I muscle fibres formation via improving mitochondrial biogenesis. In the in vivo study, a total of sixty Duroc × Landrace × Yorkshire weaning piglets with an average body weight of 6·55 (sd 0·36) kg were randomly divided into four treatments and fed with a basal diet or a basal diet supplemented with 0·5, 1·0 and 1·5 % l-Arg, respectively, in a 4-week trial. Results showed that dietary supplementation of 1·0 % Arg significantly enhanced the activity of succinate dehydrogenase, up-regulated the protein expression of myosin heavy chain I (MyHC I) and increased the mRNA levels of MyHC I, troponin I1, C1 and T1 (Tnni1, Tnnc1 and Tnnt1) in longissimus dorsi muscle compared with the control group. In addition, ATPase staining analysis indicated that 1·0 % Arg supplementation significantly increased the number of type I muscle fibres and significantly decreased the number of type II muscle fibres. Furthermore, 1·0 % Arg supplementation significantly up-regulated PPAR-γ coactivator-1α (PGC-1α), sirtuin 1 and cytochrome c (Cytc) protein expressions, increased PGC-1α, nuclear respiratory factor 1 (NRF1), mitochondria transcription factor B1 (TFB1M), Cytc and ATP synthase subunit C1 (ATP5G) mRNA levels and increased mitochondrial DNA content. In the in vitro study, mitochondrial complex I inhibitor rotenone (Rot) was used. We found that Rot annulled Arg-induced type I muscle fibres formation. Together, our results provide for the first time the evidence that Arg promotes porcine type I muscle fibres formation through improvement of mitochondrial biogenesis.
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Arginina/farmacología , Suplementos Dietéticos , Mitocondrias/efectos de los fármacos , Fibras Musculares de Contracción Lenta/efectos de los fármacos , Biogénesis de Organelos , Animales , PorcinosRESUMEN
Stretch activation (SA) is a delayed increase in force following a rapid muscle length increase. SA is best known for its role in asynchronous insect flight muscle, where it has replaced calcium's typical role of modulating muscle force levels during a contraction cycle. SA also occurs in mammalian skeletal muscle but has previously been thought to be too low in magnitude, relative to calcium-activated (CA) force, to be a significant contributor to force generation during locomotion. To test this supposition, we compared SA and CA force at different Pi concentrations (0-16 mM) in skinned mouse soleus (slow-twitch) and extensor digitorum longus (EDL; fast-twitch) muscle fibers. CA isometric force decreased similarly in both muscles with increasing Pi, as expected. SA force decreased with Pi in EDL (40%), leaving the SA to CA force ratio relatively constant across Pi concentrations (17-25%). In contrast, SA force increased in soleus (42%), causing a quadrupling of the SA to CA force ratio, from 11% at 0 mM Pi to 43% at 16 mM Pi, showing that SA is a significant force modulator in slow-twitch mammalian fibers. This modulation would be most prominent during prolonged muscle use, which increases Pi concentration and impairs calcium cycling. Based upon our previous Drosophila myosin isoform studies and this work, we propose that in slow-twitch fibers a rapid stretch in the presence of Pi reverses myosin's power stroke, enabling quick rebinding to actin and enhanced force production, while in fast-twitch fibers, stretch and Pi cause myosin to detach from actin.